Non-alcoholic fatty liver disease (NAFLD) is a common and morbid metabolic disease that independently predicts development of type II diabetes and its cardiovascular, renal and retinal diabetic complications. NAFLD is the most common chronic liver disease worldwide, and will become the most common indication for liver transplantation within the next five years. Abating the progression of this disease and its complications is hindered by the dearth of effective NAFLD treatments. Our long-term goal is to understand how metabolic pathways leading to nonalcoholic fatty liver disease (NAFLD) can be modulated to prevent the complications of progressive liver disease. We identified the hepatic carbohydrate carrier, GLUT8, as a therapeutic target because 1) GLUT8 promotes diet-induced hepatic steatosis and metabolic syndrome and 2) the disaccharide glucose ?mimetic? trehalose inhibits GLUT8 and activates an adaptive fasting response (e.g. AMP kinase and autophagy), to reverse hepatic steatosis. The objective here is to understand the mechanisms by which hepatic glucose transport modulates hepatic and whole-organism energy homeostasis. We hypothesize that hepatocyte glucose transport is a key modulator of hepatic and whole-organism metabolic homeostasis. Our preliminary data suggest: 1) GLUT8-deficient mice exhibit enhanced hepatic fasting responses, including secretion of the anti-diabetic, thermogenic hepatokine, FGF21, and 2) Trehalose blocks GLUT8 in the liver and induces hepatocyte PGC1? and FGF21 expression in correlation with enhanced thermogenesis in vivo. This proposal will thus better define the relationship between GLUT8, the GLUT8 inhibitor trehalose, and trehalose induction of hepatic FGF21 and thermogenesis. The two Specific Aims are to 1) Identify mechanisms by which GLUT8 regulates the hepatic fasting response, and 2) Define mechanisms mediating trehalose-induced thermogenesis. Successful completion of these Aims will define glucose transport regulation of fasting-state autophagy and their role in whole-organism energy homeostasis. Therefore, this work is expected to justify trehalose advancement to human trials against diabetes and NAFLD, inform clinical utility, and catalyze development of next-generation drugs leveraging trehalose and GLUT8-related pathways.